A SPECIES OF tropical fish has given researchers a new insight into the science behind addiction in a study which will help with the development of therapies that could block drug-seeking behaviour.
Scientists at the University of Utah Health devised a system that allowed zebrafish to self-administer doses of hydrocodone, an opioid that is commonly prescribed to people for pain relief.
After one week, the fish increased their drug-seeking behaviour, even when doing so required them to put themselves in risky conditions or work harder for the drug. The study also found the fish showed signs of anxiety – a hallmark of withdrawal – 48 hours after the last exposure.
The study is published in the journal Behavioral Brain Research and researchers said it could lead to new therapies to treat dependence.
The experiment involved a motion detector which the fish could trigger to release food by swimming over an active platform in their tank. An identical inactive platform was stationed on the opposite side of the tank as a control in the study. Researchers recorded the number of times the fish triggered the active platform to release the food compared to the control platform.
Then they repeated the same set-up, but instead of food, the fish that were conditioned to trigger the active platform received a dose of hydrocodone. A continuous flow of water flushed into the tank, which forced the fish to trigger the system to receive another dose of the drug. Over the course of the five days, the fish self-administered the drug during 50-minute sessions.
“The fish needed to perform an action to get the drug rather than receiving it passively,” said author Gabriel Bossé, a researcher atRandall Peterson’s lab. “Drug-seeking has been modelled before in rodents and primates, but having a model to study this in zebrafish could move the [study of addiction] forward.”
This drug-seeking behaviour also increased when the zebrafish were forced to receive the opioid in progressively shallower water, a stressful environmental setting that unconditioned fish would avoid. Fish that received a reduced dose of hydrocodone at the original depth also increased their drug-seeking behaviour to obtain an equivalent fix.
“This was important, because we forced the fish to do more work to receive [the original dose of] the drug, and they were more than willing to do more work,” said co-author Randall T Peterson, professor of pharmacology and toxicology at U of U Health.
Conditioned zebrafish treated with naloxone, a drug that blocks the μ-opioid receptor, as well as dopamine blockers, reduced their drug-seeking behaviour during the experiments.
Zebrafish share 70% of genes with humans and also share similar biological pathways that lead to addiction. Like people, they have a μ-opioid receptor and two neurotransmitters, dopamine and glutamate, that trigger the natural reward system in the brain.
For addicts, substitution therapies, which include slow acting opioids (methadone), opioids that produce a partial biological response (buprenorphine) or antagonists that block the opioid receptor (naloxone), are the only available treatments for opioid addiction are often leading to high rates of relapse.
Researchers said they will use this new model system to search for new therapeutics that could block drug-seeking behaviour. Bossé explained that the zebrafish model is scalable and could be used to rapidly screen through thousands of compounds.
In addition, researchers could manipulate the genetic make-up of zebrafish offspring to explore the specific biological pathways associated with drug-seeking behaviour.
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